Ester or amide derivatives

ABSTRACT

An ester or amide derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. Particularly, an ester or amide derivative of 4-oxo-1,4-dihydroqunoline-2-carboxylic acid represented by the general formula (I′) or (I″), or a pharmaceutically acceptable salt thereof.

TECHNICAL FIELD

The present invention relates to a novel ester or amide derivative,particularly an ester or amide derivative of4-oxo-1,4-dihydroqunoline-2-carboxylic acid, or a pharmaceuticallyacceptable salt thereof, and a drug composition containing it as anactive ingredient, particularly a preventive or remedy for Helicobacterpylori infectious diseases.

BACKGROUND ART

Helicobacter pylori is a pathogenic bacterium discovered in 1983 and iscalled a background pathogenic factor of peptic ulcers (such as gastriculcer and duodenal ulcer), inflammations (such as gastritis), diseasesof upper digestive tracts such as gastric cancer, MALT(mucosa-associated lymphoid tissue) lymphoma, or chronic heart disease.At present, studies on the therapy of Helicobacter pylori infectiousdiseases are being actively made. As the therapy, there are many reportsfor the purposes of bacterial elimination and prevention of recurrence,as described below. For example, there is numerated administration of asingle drug of, e.g., bismuth, antibiotic, proton pump inhibitor (PPI),or anti-ulcer agent, or polypharmacy (such as two-drug therapy andthree-drug therapy) comprising a combination of the foregoing drugs (seeInternal Medicine, Special Issue, Vol. 78 (1), 1996, by Nankodo).However, these therapies still involve many problems to be solved, suchas high frequency of administration of the drug(s), necessity ofadministration of a lager amount of the drug(s) than the regular dose,crisis of diarrhea or constipation by administration of the drug(s), andgeneration of resistant bacteria.

As an anti-helicobacter pylori agent, EP811613 discloses derivatives of4-oxo-1,4-dihydroquinoline or naphthyridine in terms of the followinggeneral formula. In the general formula, the substituent (R₂ group) atthe 2-position of the ring is a C₁ to C₁₀ alkyl group, a (C₁ to C₁₀alkyl)phenyl group, a C₂ to C₁₀ alkenyl group, a (C₂ to C₁₀alkenyl)phenyl group, a C₂ to C₁₀ alkynyl group, a (C₂ to C₁₀alkynyl)phenyl group, a phenyl group, a naphthyl group, a furyl group, athiophenyl group, or a pyridyl group.

Further, JP-A-10-132784 discloses the following3-methyl-4-oxo-1,4-dihydroquinone derivative as an anti-helicobacterpylori agent, in which, however, the substituent at the 2-position is anonenyl group.

However, creation of a compound having a stronger anti-helicobacterpylori action by single and oral administration is being demanded.

On the other hand, as derivatives of a3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid, in DE1913466, Pol.J. Pharmacol. Pharm., 33(5), 539-544, 1981, Indian. J. Pharm., 39(1),13-15, 1977, J. Indian Chemical Society, 50(3), 217-218, 1973, and J.Indian Chemical Society, 51(11), 967-969, 1974, there are disclosedcompounds having an ethoxycarbonyl group or a (substituted orunsubstituted) NH₂—NH—CO— group at the 2-position of the quinoline ring.However, any of these compounds are merely a synthesis intermediate orare merely reported that they have an anti-amoeba activity. Thesedocuments neither disclose nor suggest their anti-helicobacter pyloriactivity.

DISCLOSURE OF THE INVENTION

We, the present inventors made extensive and intensive investigationswith respect to compounds having an anti-helicobacter pylori activity.As a result, it has been found that novel ester or amide derivatives of4-oxo-1,4-dihydroquinoline-2-carboxylic acid, which are different interms of structure from the conventional compounds in the point that onthe 1,4-dihydroquinoline ring or 1,4-dihydronaphthyridine ring, not onlya substituent at the 2-position is an ester residue or a substitutedamide group, but also a substituent at the 3-position is an alkyl group,(1) have a strong and selective anti-bacterial action againstHelicobacter pylori, (2) have a strong anti-bacterial action againstHelicobacter pylori within digestive tracts by oral administration tomammals, and (3) are useful in the bacterial elimination therapy againstpatients infected with Helicobacter pylori.

Specifically, the invention relates to a novel ester or amide derivativerepresented by the following general formula (I) or a salt thereof:

wherein:

X¹ to X⁴ each independently represents C or N, provided that at leastone of X¹ to X⁴ represents C;

Y represents O or NH;

R¹ represents a C₁ to C₆ alkyl group;

R² represents (a) a C₁ to C₁₀ alkyl group, provided that when Xrepresents O, R² represents a C₃ to C₁₀ alkyl group, or (b) an aryl-C₁to C₁₀ alkyl group, a heteroaryl-C₁ to C₁₀ alkyl group, or acycloalkyl-C₁ to C₁₀ alkyl group, provided that any carbon-carbon bondof the C₁ to C₁₀ alkyl group may be inserted by —O—, —NR⁸—, or—S(O)_(n)—, wherein R⁸ represents H or a C₁ to C₆ alkyl group, and n is0, 1 or 2, and that the aryl, heteroaryl and cycloalkyl may each besubstituted with from one to three of halogen, C₁ to C₆ alkyl, C₁ to C₆alkyl-O—, nitro, cyano, amino, hydroxycarbonyl, C₁ to C₆ alkyl-NH—, ordi-C₁ to C₆ alkyl=N—;

R³ represents H, a C₁ to C₆ alkyl group, an aryl-C₁ to C₆ alkyl group, aheteroaryl-C₁ to C₆ alkyl group, a cycloalkyl-C₁ to C₆ alkyl group, anaryl group, a heteroaryl group, or a cycloalkyl group, provided that thearyl, heteroaryl and cycloalkyl may each be substituted with from one tothree of halogen, C₁ to C₆ alkyl, C₁ to C₆ alkyl-O—, nitro, cyano,amino, hydroxycarbonyl, C₁ to C₆ alkyl-NH—, or di-C₁ to C₆ alkyl=N—; and

R⁴ to R⁷ may be the same or different and each represents H, a halogen,a nitro group, a cyano group, an amino group, a hydroxycarbonyl group, aC₁ to C₆ alkyl group, a C₁ to C₆ alkyl-O— group, a C₁ to C₆ alkyl-NHgroup, or a di-C₁ to C₆ alkyl=N— group,

provided that in the case where X¹ to X⁴ each represents N, R⁴ to R⁷ tobe bound thereto are not present and that R³ and R⁴ may be takentogether to form a linear or branched C₁ to C₈ alkylene which may beinserted by N, O or S.

Also, the invention relates to a drug composition comprising the esteror amide derivative represented by the foregoing general formula (I) orits pharmaceutically acceptable salt and a pharmaceutically acceptablecarrier, a particularly a drug composition as a preventive or remedy forHelicobacter pylori infectious diseases.

The compound (I) of the invention is structurally characterized in thata substituent at the 2-position of the 1,4-dihydroquinoline ring or1,4-dihydronaphthyridine ring is an ester residue or an substitutedamide group and is superior to the known compounds having a hydrocarbongroup as the substituent at the 2-position in the point that itundergoes strong bacterial elimination against Helicobacter pyloriwithin digestive tracts by oral administration to mammals.

The compound (I) of the invention will be hereunder described in detail.

Examples of the “halogen” include a fluorine atom, a chlorine atom, abromine atom, and an iodine atom.

The term “alkyl” means a linear or branched saturated hydrocarbon group.Specific examples of the C₁ to C₁₀ alkyl include a methyl group, anethyl group, a propyl group, a butyl group, a pentyl group, a hexylgroup, a heptyl group, an octyl group, a nonyl group, a decyl group, andstructural isomers thereof (such as an isopropyl group). Specificexamples of the C₁ to C₆ alkyl include a methyl group, an ethyl group, apropyl group, a butyl group, a pentyl group, a hexyl group, andstructural isomers thereof (such as an isopropyl group). Specificexamples of the C₆ to C₈ alkyl include a hexyl group, a heptyl group, anoctyl group, and structural isomers thereof (such as a methylhexylgroup).

The term “alkylene” means a divalent group resulted from removal ofhydrogen from the foregoing alkyl. Specific examples of the C₁ to C₈alkylene include methylene, ethylene, propylene, butylene, pentylene,hexylene, heptylene, octylene, and structural isomers thereof (such as2-methylpropylene).

The term “aryl” means an aromatic hydrocarbon group, and preferably a C₆to C₁₄ aryl. Specific examples include phenyl, naphthyl, and biphenyl,and particularly preferably phenyl.

The term “heteroaryl” means a 5-membered or 6-membered monocyclicheteroaryl having from 1 to 4 hetero atoms selected from N, S and O, ora bicyclic heteroaryl fused with a benzene ring, which may be partiallysaturated. Examples of the monocyclic heteroaryl include furyl, thienyl,pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyridyl,pyrazinyl, pyrimidyl, triazolyl, thiazolyl, pyridazinyl, triazinyl,oxazolyl, and pyrimidyl. Examples of the bicyclic heteroaryl includebenzofuranyl, benzothienyl, benzothiadiazoyl, benzothiazolyl,benzoimidazolyl, indolyl, quinolyl, isoquinolyl, and quinoxalinyl. Ofthese are preferable 5-membered or 6-membered monocyclic heteroaryls,with furyl, thienyl, imidazolyl, thiazolyl and pyridyl being morepreferable.

The term “cycloalkyl” means a saturated hydrocarbon group having from 3to 8 carbon atoms. Specific examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

In the general formula of the invention, specific examples of the ringrepresented by the formula:

In the invention, a quinoline ring is particularly preferable.

In the invention, is preferable a compound represented by the foregoinggeneral formula (I) wherein X¹ to X⁴ are all C, and specifically anester or amide derivative of3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid represented by thefollowing general formula (I′) or a salt thereof.

In the general formula, X¹ to X⁴, Y, and R¹ to R⁷ have the same meaningsas defined above.

In the invention, is more preferable a compound represented by theforegoing general formula (I) wherein X¹ to X⁴ are all C, and R³ is H,and specifically an ester or amide derivative of3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid represented by thefollowing general formula (I″) or a salt thereof.

In the general formula, X¹ to X⁴, Y, and R⁴ to R⁷ have the same meaningsas defined above.

In the invention, is further preferable a compound represented by theforegoing general formula (I″) wherein R² represents (a) a C₁ toC₁₀alkyl group (provided that when X is O, R² represents a C₅ toC₁₀alkyl group), or (b) a phenyl-C₁ to C₆ alkyl group (provided that anycarbon-carbon bond of the C₁ to C₁₀ alkyl group may be inserted by —O—,—NR⁸—, or —S(O)_(n)— (wherein R⁸ represents H or a C₁ to C₆ alkyl, and nis 0, 1 or 2), and that the phenyl may be substituted with from one tothree of halogen, C₁ to C₆ alkyl, C₁ to C₆ alkyl-O—, nitro, amino, C₁ toC₆ alkyl-NH—, or di-C₁ to C₆ alkyl=N—); and more preferably, R²represents a C₆ to C₈ alkyl group or a benzyl group which may besubstituted with one to three of halogen, C₁ to C₆ alkyl, C₁ to C₆alkyl-O—, nitro, amino, C₁ to C₆ alkyl-N—, or di-C₁ to C₆ alkyl=N—.

Also, a compound wherein R¹ represents a methyl group is preferable. Acompound wherein R⁴ to R⁷ are all H is preferable.

In the invention, the following compounds are particularly preferable.

N-Heptyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

N-(4-Methylbenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

N-(3-Methoxybenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

Benzyl 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate

With respect to the compound of the invention, there are optical isomers(such as optically active compounds and diastereomers) depending on thekinds of the groups. Further, the compound of the invention includes acompound having an amide bond. There may be tautomers based on the amidebond. Especially, among the compounds of the invention, the ester oramide derivatives of 3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylicacid represented by the general formula (I″) include the followingtautomers.

The invention includes isolated isomers and mixed isomers thereof.

The compound (I) of the invention may form a salt with an acid or a basedepending on the kinds of the substituents. Such a salt is apharmaceutically acceptable salt. Specific examples include acidaddition salts with an inorganic acid such as hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, andphosphoric acid, or with an organic acid such as formic acid, aceticacid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaricacid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid,methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamicacid; salts with an inorganic base such as sodium, potassium, magnesium,calcium, and aluminum, or with an organic base such as methylamine,ethylamine, ethanolamine, lysine, and ornithine; and ammonium salts.

In addition, the invention includes various hydrates, solvates andcrystal polymorphisms of the compound (I) of the invention and its salt.Moreover, the invention includes prodrugs of the substance of theformula (I) as obtained in the customary means. The prodrugs as usedherein mean a compound having a substituent(s) capable of convertinginto the substituent(s) of the substance of the formula (I) bysolvolysis or under physiological conditions, especially a compound thatwill be converted into the substance of the formula (I) within a livingbody. As the substituent to form the prodrug are enumerated those groupsdescribed in Prog. Med., 5, 2157-2161 (1985) and Iyakuhin No Kaihatsu(Development of Drugs), Vol. 7, “Molecular Design”, 163-198 (1990), byHirokawa-shoten.

For example, there is enumerated a compound having a hydroxyl groupsubstituted at the 1-position of the quinoline ring of the ester oramide derivative of 3-alkyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid(I″).

Production Process

The compound (I) and its salt of the invention can be produced throughapplication of various known synthesis processes by utilizing thecharacteristic features based on the basic skeleton thereof or kinds ofthe substituents.

First process

Among the compounds of the invention, an amide derivative (Ia) having asubstituted amino group as the substituent at the 2-position of the1,4-dihydroquinoline ring is produced by reacting a carboxylic acidderivative represented by the general formula (II) with an aminerepresented by the general formula (III) to form an amide bond.

In the formulae, X¹ to X⁴ and R¹ to R⁷ have the same meanings as definedabove.

The reaction is usually carried out in a usual solvent such as acetone,dioxane, tetrahydrofuran, diethyl ether, diisopropyl ether,acetonitrile, chloroform, dichloromethane, 1,2-dichloroethane, ethylacetate, N,N-dimethylformamide (DMF), toluene, and pyridine, or amixture thereof. The reaction may also be carried out in other arbitraryorganic solvent so far as it does not adversely affect the reaction.Although the reaction temperature and reaction time are not particularlylimited, the reaction is usually carried out at room temperatureovernight. The reaction can be carried out in the presence of a catalystsuch as 1-hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine(DMAP), and/or a condensing agent such as dicyclohexylcarbodiimide(DCC), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride(WSCD.HCl), and carbonyldiimidazole (CDI). Further, the reaction canalso be carried out in the presence of N,N-dimethylformamide (DMF) viaan acid chloride using thionyl chloride or oxalyl chloride.Alternatively, the reaction can be carried out via an active ester usingan acid anhydride such as acetic anhydride, or an acid chloride such asmesyl chloride.

Second Process

Among the compounds of the invention, an ester derivative (Ib) having anester residue as the substituent at the 2-position of the1,4-dihydroquinoline ring is produced by reacting the carboxylic acidderivative represented by the general formula (II) with an alcoholrepresented by the general formula (IV) to form an ester bond.

In the formulae, X¹ to X⁴ and R¹ to R⁷ have the same meanings as definedabove.

The reaction is usually carried out in the foregoing usual solvent or amixture thereof. The reaction may also be carried out in other arbitraryorganic solvent so far as it does not adversely affect the reaction.Although the reaction temperature and reaction time are not particularlylimited, the reaction is usually carried out at room temperatureovernight. The reaction can be carried out in the presence of a catalystsuch as 1-hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine(DMAP), and/or a condensing agent such as dicyclohexylcarbodiimide(DCC), 1-[3-(dimethylamino)propyl-3-ethylcarbodiimide hydrochloride(WSCD.HCl), and carbonyldiimidazole (CDI). Further, the reaction canalso be carried out in the presence of N,N-dimethylformamide (DMF) viaan acid chloride using thionyl chloride or oxalyl chloride.Alternatively, the reaction can be carried out via an active ester usingan acid anhydride such as acetic anhydride, or an acid chloride such asmesyl chloride.

Incidentally, with respect to the compound of the invention, asdescribed above, there may be the case where isomers such as a racemate,an optically active compound, and a diastereomer are present singly oras a mixture. The racemic compound can be introduced into astereochemically pure isomer by using a proper starting material(s), orby general racemic resolution (such as a method in which the racemiccompound is introduced into a diastereomer salt with a general opticallyactive acid (such as tartaric acid), which is then subjected to opticalresolution). Further, the mixture of diastereomers can be separated by acustomary manner such as fractional crystallization and chromatography.

INDUSTRIAL APPLICABILITY

The invention exhibits a selective anti-bacterial action againstHelicobacter pylori and is effective for the therapy of infections ofHelicobacter pylori in human being and related bacteria belonging to thegenus Helicobacter in animals. Further, the anti-helicobacter pyloriagent of the invention is effective for prevention (including preventionof recurrence) or therapy of peptic ulcers (such as gastric or duodenalulcer), inflammations (such as acute or chronic gastritis orduodenitis), diseases of upper digestive tracts such as gastric cancer,MALT (mucosa-associated lymphoid tissue) lymphoma, or chronic heartdisease.

The actions of the compound of the invention were confirmed by thefollowing pharmacological tests.

(1) In Vitro Anti-bacterial Activity Test

1) Preparation of Anti-bacterial Substance-containing Agar Plate

A substance to be evaluated was dissolved in 100% DMSO, and the solutionwas subjected to two-fold series dilution. The diluted solution wascharged in a sterilized round Petri dish, to which was then added 10 mLof a brucella agar medium (0.1% β-cyclodextrin or 5% sheep blood) whichhad been sterilized and kept at 50° C. After intimate mixing, themixture was solidified. The ultimate concentration of DMSO is 1% orless.

2) Preparation of Inoculation Material and Result Judgment

Helicobacter pylori, such as Helicobacter pylori ATCC43504, which hadbeen cultured at 37° C. for 3 days in a multigas incubator (N₂: 80%,CO₂: 15%, O₂: 5%) using a brucella agar medium (containing 5% calfserum), was prepared using a brucella broth such that the number ofbacteria was about 10⁸ per mL depending on the turbidity. The bacterialsolution was similarly diluted with a brucella broth 100-fold, about 1or 5 μL of which was then inoculated on the surface of a drug-containingagar medium using a micro-planter. The inoculated agar plate wascultured at 37° C. for 3 days (72 hours) in the foregoing multigasincubator. The cultured agar plate was observed, and a minimal drugconcentration at which the proliferation was not observed was designatedas MIC.

(2) In Vivo Anti-bacterial Activity Test

The infection test was carried out by using Mongolian gerbils asreported to be stably infected (J. Gastroenterology 31: supple IX,24-28, 1996). An overnight cultured inoculum of ATCC43504 was inoculatedinto a stomach of overnight-fasted Mongolian gerbils(MGS/Sea, male,4-week-old) About one week after the infection, the therapy was startedby orally administering a drug to be evaluated dissolved in a solventaccording to the customary manner in a dose of 10 mg/kg, 3 mg/kg or 1mL/kg twice per day for three days. Next day after completion of theadministration, the stomach was taken out and ground. A stomachhomogenate solution was subjected to 10-fold series dilution, inoculatedon a modified Skirrow medium, and then cultured at 37° C. for six toseven days under microaerophile conditions or 10% CO₂ conditions. Thenumber of bacteria within the stomach was calculated from the number ofgrown bacteria.

Any of the compounds of Examples 1 to 4 of the invention exhibited abacterial elimination effect from at a dose of 1 mg/kg. On the otherhand, the following known compounds exhibited a bacterial eliminationeffect from at a does of 10 mg/kg.

Accordingly, it was confirmed that the compounds of the invention have astronger bacterial elimination effect by oral administration to mammalsas compared with the known anti-helicobacter pylori agents.

The drug containing the compound (I) of the invention or its salt and apharmaceutically acceptable carrier can be prepared by a usuallyemployed method using one or two or more of the compound represented bythe general formula (I) or its salt and a pharmaceutical carrier,excipient and other additives as used for formulation. Theadministration may be in any form of oral administration by tablets,pills, capsules, granules, powders, liquids, etc., or parenteraladministration by injections such as intravenous or intramuscularinjection, suppositories, dermal administration, etc.

As a solid composition for the oral administration according to theinvention, tablets, powders, or granules are used. In such a solidcomposition, one or more active substances are mixed with at least oneinert diluent such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone,magnesium metasilicate aluminate. The composition may contain additivesother than the inert diluent, such as a lubricant such as magnesiumstearate, a disintegrating agent such as cellulose calcium glycolate, astabilizer such as lactose, and a dissolution aid such as glutamic acidand aspartic acid, according to the customary method. If desired, thetablets or pills may be coated by a sugar coating such as sugar,gelatin, hydroxypropyl cellulose, and hydroxypropylmethyl cellulosephthalate, or a film made of a gastric-soluble or intestinal solublesubstance.

The liquid composition for oral administration contains apharmaceutically acceptable emulsion agent, solution agent, suspendingagent, syrup, or elixir and contains a generally employed inert diluentsuch as purified water and ethanol. In addition to the inert diluent,this composition may contain an auxiliary agent such as a wetting agentand a suspending agent, a sweetener, a flavor, an aromatic, or anantiseptic.

The injection for parenteral administration contains a sterile aqueousor non-aqueous solution agent, suspending agent or emulsion agent.Examples of the aqueous solution agent or suspending agent includedistilled water or physiological saline for injection. Examples of thenon-aqueous solution agent or suspending agent include propylene glycol,polyethylene glycol, vegetable oils such as olive oil, alcohols such asethanol, and Polysolvate 80 (trade name). Such a composition may alsocontain an auxiliary agent such as an antiseptic, a wetting agent, anemulsifier, a dispersing agent, a stabilizer (such as lactose), and adissolution aid (such as glutamic acid and aspartic acid). Thesecompositions are sterilized by, for example, filtration through abacteria-holding filter, compounding with an anti-bacterial agent, orirradiation. Further, these can be used by producing a sterile solidcomposition and dissolving it in sterile water or a sterile solvent forinjection before the used.

Usually, in the case of the oral administration, it is proper that thedose of the drug per day is from about 0.001 to 30 mg per kg, andpreferably from 0.1 to 5 mg per kg of the body weight and that the drugis administered once or dividedly two to four times. In the case of theintravenous administration, it is proper that the dose of the drug perday is from about 0.001 to 30 mg per kg of the body weight and that thedrug is administered once or dividedly several times. The dose isproperly determined depending on the individuals while taking intoconsideration the symptom, age and sex.

According to the invention, the compound (I) can be used singly or incombination with other anti-bacterial agents (preferably one to threekinds). Such other anti-bacterial agents can be used in combinationsimultaneously with the compound of the invention or after elapsing fora while.

Examples of such other anti-bacterial agents include nitroimidazoleantibiotics (such as tinidazole and metronidazole), tetracycline seriesdrugs (such as tetracycline, minocycline, and doxycycline), penicillinseries drugs (such as amoxicillin, ampicillin, talampicillin,bacampicillin, lenampicillin, mezlocillin, and sultamicillin),cephalosporin series drugs (such as cefaclor, cefadroxil, cefalexin,cefpodoxime proxetil, cefixime, cefdinir, ceftibuten, cefatiam hexetil,cefetamet pivoxil, cefcapene pivoxil, sefiditoren pivoxil, and cefloximeaxetil), penenm series drugs (such as faropenem and ritipenem acoxil),macrolide series drugs (such as erythromycin, oleandomycin, josamycin,midecamycin, rokitamycin, clarithromycin, roxithromycin, terithromycin,and azithromycin), lincomycin series drugs (such as lincomycin andclindamycin), aminoglycocide series drygs (such as paromomycin),quinolone series drugs (such as ofloxacin, lebofloxacin, norfloxacin,enoxacin, ciprofloxacin, lomefloxacin, tosufloxacin, fleroxacin,spafloxacin, temafloxacin, nadifloxacin, grepafloxacin, balfloxacin,prulifloxacin, gatifloxacin, sitafloxacin, and pazufloxacin), andnitrofurantoin. Further, combinations of the compound (I) of theinvention with PPI (such as omeprazole, rabeprazole, and lansoprazole)or anti-ulcer agents (such as H₂ antagonists such as ranitidine,cimetidine, and famotidine, or gastric mucosal protective agents) fallwithin the scope of the invention.

BEST MODE FOR CARRYING OUT THE INVENTION

The invention will be described below in more detail with reference tothe Referential Examples and Examples. As a matter of course, it shouldnot be construed that the invention is limited thereto. In the nuclearmagnetic resonance spectra (1H-NMR) described in physical properties,DMSO was used as a measurement solvent, and tetramethyl silane was usedas an internal standard (δ: 0.00 ppm). The mass analysis (MS) was madeby the fast atom bombardment (FAB).

REFERENTIAL EXAMPLE 1 Ethyl3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate

(1) Aniline (51.1 g) and 21.4 g of Diethyl oxalpropionate were dissolvedin 200 mL of benzene, to which was then added 4 mL of acetic acid, andthe mixture was refluxed upon heating overnight by a Dean-Starkcondenser. The solvent was distilled off to obtain a yellow oilysubstance.

(2) The compound obtained in (1) was dissolved in 200 mL of diphenylether, and the solution was heated at 250° C. for 30 minutes. Afterallowing to stand for cooling, the reaction mixture was poured into 600mL of hexane, and precipitates were filtered out. The crystals wererinsed with diethyl ether and dried to obtain 36.7 g (63%) of the titledcompound. MS: 232 (M⁺+1)

REFERENTIAL EXAMPLE 2 3-Methyl-4-oxo-1,4-dihydroquinoline-2-carboxylicacid

To 18.1 g of the compound obtained in Referential Example 1 was added170 mL of a 1N sodium hydroxide aqueous solution, and the mixture wasrefluxed upon heating for 30 minutes. After allowing to stand forcooling, hydrochloric acid (concentrated hydrochloric acid:water=1:1)was gradually added, and precipitates were collected by filtration andrinsed with dilute hydrochloric acid, followed by drying. To theresulting crystals was added 100 mL of acetonitrile, and the mixture wasrefluxed upon heating for 30 minutes. After allowing to stand forcooling, crystals were collected by filtration and dried to obtain 15.6g (98%) of the titled compound. MS: 202 (M⁺−1)

EXAMPLE 1 N-Heptyl-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

The compound (3.252 g) obtained in Referential Example 2, 2.39 g ofHOBt, and 3.385 g of WSCD were dissolved in 40 mL of DMF. After dropwiseaddition of 2.041 g of heptylamine, the reaction mixture was stirredovernight. Saturated sodium chloride aqueous solution and ethyl acetatewere added, and the mixture was stirred for one hour. Precipitates werecollected by filtration, rinsed with dilute hydrochloric acid, ethylacetate, and water, and then dried to obtain 4.437 g (92%) of the titledcompound.

1H-NMR: 0.87 (t, 2H), 1.28 to 1.34 (m, 8H), 1.51 to 1.58 (m, 2H), 1.98(s, 3H), 3.27 (q, 2H), 7.27 to 7.31 (m, 1H), 7.58 to 7.65 (m, 2H), 8.08to 8.10 (m, 1H), 8.81 (t, 1H), 11.84 (s, 1H)

MS (m/z): 301 (M⁺+1)

Compounds of the Examples 2 to 5 were obtained in the same manner as inExample 1.

EXAMPLE 2N-(4-Methylbenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

1H-NMR: 1.96 (s, 3H), 2.30 (s, 3H), 4.46 (d, 2H), 7.18 (d, 2H), 7.27 to7.31 (m, 3H), 7.60 to 7.65 (m, 2H), 8.09 (d, 1H), 9.32 (s, 1H), 11.89(s, 1H)

MS (m/z): 307 (M⁺+1)

EXAMPLE 3N-(3-Methoxybenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

1H-NMR: 1.99 (s, 3H), 3.76 (s, 3H), 4.50 (d, 2H), 6.85 to 6.87 (m, 1H),6.96 to 6.97 (m, 2H), 7.27 to 7.32 (m, 2H), 7.60 to 7.65 (m, 2H), 8.09(d, 1H), 9.35 (t, 1H), 11.91 (s, 1H)

MS (m/z): 323 (M⁺+1)

EXAMPLE 4N-{2-[Ethyl-(3-methylphenyl)amino]ethyl}-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

1H-NMR: 1.10 (t, 3H), 1.99 (s, 3H), 2.24 (s, 3H), 3.39 (q, 2H), 3.45 (s,4H), 6.42 (d, 1H), 6.59 to 6.62 (m, 2H), 7.05 (t, 1H), 7.28 to 7.32 (m,1H), 7.60 to 7.66 (m, 2H), 8.09 (d, 2H), 8.95 (s, 1H), 11.86 (s, 1H)

MS (m/z): 364 (M⁺+1)

EXAMPLE 5N-(4-Phenylbutyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide

1H-NMR: 1.53 to 1.70 (m, 4H), 1.96 (s, 3H), 2.63 (t, 2H), 3.29 to 3.34(m, 2H), 7.16 to 7.30 (m, 6H), 7.57 to 7.64 (m, 2H), 8.09 (d, 1H), 8.83(t, 1H), 11.83 (s, 1H)

MS (m/z): 335 (M⁺+1)

EXAMPLE 6 Benzyl 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate

The compound (5.615 g) obtained in Referential Example 2, 4.209 g ofHOBt, 5.879 g of WSCD, and 138 mg of DMAP were dissolved in a mixedsolvent of 55 mL of methylene chloride and 20 mL of DMF. After dropwiseaddition of 3.341 g of benzyl alcohol, the reaction mixture was stirredovernight, to which was then added saturated sodium chloride aqueoussolution. Precipitates were collected by filtration, rinsed with ethylacetate and water, and then dried to obtain 5.109 g (63%) of the titledcompound.

1H-NMR: 2.19 (s, 3H), 5.49 (s, 3H), 7.31 to 7.35 (m, 1H), 7.37 to 7.46(m, 3H), 7.53 to 7.55 (m, 2H), 7.65 to 7.69 (m, 1H), 7.81 (d, 1H), 8.08to 8.10 (m, 1H), 11.78 (s, 1H) MS (m/z): 294 (M⁺ +1)

Further, the compounds represented by the chemical structural formulaein the table can be easily produced in substantially same manners as inthe Examples or production processes, or by undergoing slightmodifications within the range obvious to those skilled in the art.Incidentally, symbols shown in the table have the following meanings.No.: compound number, Me: methyl, Cl: chloro, F: fluoro

(I)

No X¹ X² X³ X⁴ Y R¹ R² R³ R⁴ R⁵ R⁶ R⁷  1 C C C C NH Me

H H H H H  2 C C C C NH Me

H H H H H  3 C C C C NH Me

H H H H H  4 C C C C NH Me

H H H H H  5 C C C C NH Me

H H H H H  6 C C C C NH Me

H H H H H  7 C C C C NH Me

H H H H H  8 N C C C NH Me

H — H H H  9 N C N C NH Me

H — H — H 10 C C C C NH Me

Me H H H H 11 C C C C NH Me

H H H H 12 C C C C NH Me

H H H H 13 C C C C NH Me

F H 14 C C C C O Me

Me H H H H 15 C C C C O Me

H H H H 16 C C C C O Me

H H H H 17 N C C C O Me

H — H H H 18 C C C C O Me

H H H — H 19 C N C C O Me

H H — H H 20 C C C C O Me

F H

What is claimed is:
 1. An amide derivative represented by the followingformula (I) or a pharmaceutically acceptable salt thereof:

wherein: X¹ to X⁴ each independently represents C; Y represents NH; R¹represents a C₁ to C₆ alkyl group; R² represents (a) a C₁ to C₁₀ alkylgroup, or (b) an aryl-C₁ to C₁₀ alkyl group, a heteroaryl-C₁ to C₁₀alkyl group, or a cycloalkyl-C₁ to C₁₀ alkyl group, provided that the C₁to C₁₀ alkyl group may be any carbon-carbon bond of the C₁ to C₁₀ alkylgroup may be inserted by —O—, —NR⁸—, or —S(O)n—, wherein R⁸ represents Hor a C₁ to C₆ alkyl group, and n is 0, 1 or 2, and that the aryl,heteroaryl and cycloalkyl may each be substituted with from one to threeof halogen, C₁ to C₆ alkyl, C₁ to C₆ alkyl-O—, nitro, cyano, amino,hydroxycarbonyl, C₁ to C₆ alkyl-NH—, or di-C₁ to C₆ alkyl=N—; R³represents H, a C₁ to C₆ alkyl group, an aryl-C₁ to C₆ alkyl group, aheteroaryl-C₁ to C₆ alkyl group, a cycloalkyl-C₁ to C₆ alkyl group, anaryl group, a heteroaryl group, or a cycloalkyl group, provided that thearyl, heteroaryl, and cycloalkyl group may each be substituted with fromone to three of halogen, C₁ to C₆ alkyl, C₁ to C₆ alkyl-O—, nitro,cyano, amino, hydroxycarbonyl, C₁ to C₆ alkyl-NH—, or di-C₁ to C₆alkyl=N—; and R⁴ to R⁷ may be the same or different and each representsH, a halogen, a nitro group, a cyano group, an amino group, ahydroxycarbonyl group, a C₁ to C₆ alkyl group, a C₁ to C₆ alkyl-O—group, a C₁ to C₆ alkyl-NH group, or a di-C₁ to C₆ alkyl=N— group,provided that R³ and R⁴ may be taken together to form a linear orbranched C₁ to C₈ alkylene which may be inserted by N, O or S.
 2. Theamide derivative or its pharmaceutically acceptable salt according toclaim 1, wherein R₃ is H.
 3. The amide derivative or itspharmaceutically acceptable salt according to claim 1, wherein R₂represents (a) a C₁ to C₁₀ alkyl group, provided that when X is O, R₃represents a C₅ to C₁₀ alkyl group, or (b) a phenyl-C₁ to C₆ alkylgroup, provided that the C₁ to C₆ alkyl may be any carbon-carbon bond ofthe C₁ to C₁₀ alkyl group may be inserted by —O—, —NR₈—, or —S(O)n—,wherein R₈ represents H or a C₁ to C₆ alkyl and n is 0, 1 or 2, and thatthe phenyl may be substituted with from one to three of halogen, C₁ toC₆ alkyl, C₁ to C₆ alkyl —O—, nitro, amino, C₁ to C₆ alkyl-NH—, or di-C₁to C₆ alkyl=N—.
 4. The amide derivative or its pharmaceuticallyacceptable salt according to any of claims 1 and 2 to 3, wherein R₂represents (a) a C₆ to C₈ alkyl group or (b) a benzyl group which may besubstituted with one to three of halogen, C₁ to C₆ alkyl, C₁ to C₆alkyl-O—, nitro, amino, C₁ to C₆ alkyl-NH—, or di-C₁ to C₆ alkyl=N—. 5.The amide derivative or its pharmaceutically acceptable salt accordingto any of claims 1 and 2 to 5, wherein R₄ to R₇ are all H.
 6. The amidederivative or its pharmaceutically acceptable salt according to any ofclaims 1 and 2 to 5, wherein R₄ and R₇ are all H.
 7. The amidederivative or its pharmaceutically acceptable salt according to any ofclaims 1 and 2 to 6, which isN-heptyl-3-methyl4-oxo-1,4-dihydroquinoline-2-carboxamide,N-(4-methylbenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide,N-(3-methoxybenzyl)-3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxamide,benzyl 3-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate, or a saltthereof.
 8. A drug composition comprising an amide derivativerepresented by the foregoing general formula (I) according to claim 1 orits pharmaceutically acceptable salt and a pharmaceutically acceptablecarrier.
 9. The drug composition according to claim 8, which ispreventative or remedy for Helicobacter pylori infectious diseases.